BIOLOGIC AGENTS AND IMMUNOTHERAPY IN RHEUMATOID ARTHRITIS: Progress and Perspective

Advances in our understanding of rheumatoid synovitis have been coupled with increasingly refined methods from biotechnology to produce promising therapeutic agents. Monoclonal antibodies (MoAbs), recombinant cytokines, cytokine receptor fusion proteins, and other biologics have moved from the status of novel reagents applied in phase I toxicity trials to, in some cases, substantially evaluated and validated tools awaiting federal regulatory approval. Biologic agents will soon be released for the treatment of patients with rheumatoid arthritis (RA). This article will be directed toward clinicians who manage patients with RA and investigators engaged in studies of RA therapeutic interventions. Attention will be directed toward selected preclinical studies as well as trials already completed in human subjects. We will focus on findings that appear promising for further investigation or where important lessons have been learned. We will review strategies for RA intervention and make recommendations regarding the design and evaluation of future therapeutic trials. We will also speculate on the potential role for biologics in future management of patients with RA. The various cells and molecules engaged in rheumatoid synovitis are well known to students of this disease. 33,80,83 Each can be considered a potential target for therapeutic intervention. 59,127 Biologic agents known to be under consideration in RA therapeutic trials are outlined in Table 1. These RA trials reflect in part the historical availability of MoAbs, recombinant cytokines, and other biotechnology-derived agents as well as an emerging sophistication in our understanding of the apparently critical targets [e.g., TNF α , T-cell receptor (TCR)] or "leverage points" in the disease process. In addition, the biologic products developed thus far reflect an evolving capacity for the biotechnology industry to synthesize and humanize therapeutic agents which maximize the efficacy/toxicity relationship (therapeutic index). Therapeutic strategies for RA intervention are shown in the list that follows. 1Inhibition of cellular function Nondepleting anti-T-cell MoAb Anti-activation/costimulation/adhesion MoAb Recombinant anti-inflammatory cytokine 2Inhibition of cytokine/receptor function Blocking MoAb to proinflammatory cytokine or receptor Inhibition of cytokine synthesis or expression Cytokine receptor administration Cytokine receptor fusion protein Competing peptide receptor antagonist Inhibition of cytokine-induced intracellular signaling 3Immune deviation (TH1 to TH2 phenotype) Recombinant anti-inflammatory cytokine 4Inhibition of major histocompatibility complex (MHC)/Ag/TCR interaction Anti-activation/adhesion/costimulation MoAb MHC antagonists TCR peptide vaccine 5Tolerance induction Antigen (Ag) administration, mucosal (oral, intranasal) or parenteral Recombinant anti-inflammatory cytokine 6Modulation of growth control/apoptosis/angiogenesis Induction of apoptosis genes and gene products Inhibition of growth factors/receptors promoting angiogenesis and cellular proliferation This list categorizes the approaches utilized in prior studies and provides a conceptual framework for consideration of future studies. It is our belief that greater clarity regarding important therapeutic targets and improved products in the research and development pipeline justify optimism regarding future therapy of RA.